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Research first: Study identifies how the microbiome is disrupted by IBD

Jul 31, 2019

The biochemical and molecular events that disrupt the microbiome and trigger immune responses during flare-ups of inflammatory bowel disease (IBD) have been observed and reported by scientists for the first time, say those behind the study.

Researchers from the Harvard T.H. Chan School of Public Health and the Broad Institute of MIT and Harvard developed a unique biotechnology toolbox to understand why microbiomes change during IBD.

They studied 132 participants for one year and compared Crohn's disease and ulcerative colitis (UC) patients to a control group of participants that did not have IBD.

Participants provided stool samples every two weeks, blood samples once a quarter, and a set of colon biopsies at the start of the study. In total, 2,965 stool, biopsy, and blood samples were analysed with an unprecedented suite of molecular, cellular, and clinical tools to understand the detailed biochemistry of the disease.

First, these detailed measurements made it easy to observe and confirm findings from previous studies, such as a reduction in overall gut ecological diversity and the gain and loss of specific "pro-" and "anti-inflammatory" microbes during disease.

More importantly, researchers were able to determine the reasons for the changes.

Findings

The results, published in Nature, show that during periods of disease activity, people with IBD had fewer microbially-derived chemicals, which researchers speculated could be due to less beneficial microbial metabolism, poorer nutrient absorption, greater water or blood levels in the bowels, and more urgent bowel movements.

These factors decreased the overall stability of the gut microbial ecosystem, leading to more episodes of improper immune responses and overreaction to the normal gut microbiome among IBD patients.

Specifically, during periods of disease activity people with IBD had higher levels of polyunsaturated fatty acids, including adrenate and arachidonate. The researchers also discovered that nicotinuric acid was found almost exclusively in the stool of patients with IBD and that levels of vitamins B5 and B3 were particularly depleted in the gut of people with IBD.

The team also found that bile acids -- a set of compounds made by humans but chemically modified by gut microbes -- were disrupted during IBD as well, in tandem with molecular regulation in groups of microbes. These included a group of bacteria related to the genus Subdoligranulum that are carried by almost everyone, but are depleted during inflammation, and which have not been previously isolated or characterized.

Overall, the findings provide the most detailed snapshot to date of the microbiome in people with IBD, during active and non-active disease states. The findings showed that different forms of IBD -- Crohn's disease compared with ulcerative colitis, for instance -- had different effects on the activity and composition of the microbiome.

The researchers said the findings provide promising new targets for potential IBD treatments, including polyunsaturated fatty acids, bile acid derivatives, and human immune response pathways, as well as new data, tools, and protocols that will enable future research on IBD and the microbiome.

"Given how tightly connected the microbiome is with our health and wellbeing, these results shed some light on how we might avoid the problems that arise when this relationship goes awry, and how we might be better stewards of these life-long companions," said Jason Lloyd-Price, who worked on the study while a research scientist at Harvard Chan School and the Broad Institute and was lead author of the paper.

The first phase of the HMP was launched in 2007 by the National Institutes of Health (NIH) Common Fund, aimed to characterize the microbiome in healthy adults and in people with specific microbiome-associated diseases.

The most recent phase of work began in 2013 with support from across the NIH, and with the mandate to tease apart the molecular mechanisms underlying the microbiome's roles in disease.

"The Human Microbiome Project overall has been a flagship effort in understanding the microbiome's contributions to health, and in creating a community of researchers who can study the microbiome to discover new diagnostics and therapies for disease," said Curtis Huttenhower, professor of computational biology and bioinformatics at Harvard Chan School and associate member at the Broad Institute and senior author of the study. "Our results from this study pave the way for early detection of upcoming flares in disease activity -- which can then be aggressively treated -- or potentially for new biochemical therapeutic opportunities to encourage complete remission of IBD."

Prevalence of IBD

IBD affects more than 3.5 million people worldwide and is growing in prevalence. IBD is a chronic disease that is marked by periods of remission followed by flare-ups in which the disease becomes active.